Sasaki, YusukeOhta, MasayukiDesai, DhruvFigueiredo, Jose-LuizWhelan, Mary C.Sugano, TomohiroYamabi, MasakiYano, WataruFaits, TylerYabusaki, KatsumiZhang, HengminMlynarchik, Andrew K.Inoue, KeisukeMizuno, KenAikawa, Masanori2015-08-032015Sasaki, Y., M. Ohta, D. Desai, J. Figueiredo, M. C. Whelan, T. Sugano, M. Yamabi, et al. 2015. “Angiopoietin Like Protein 2 (ANGPTL2) Promotes Adipose Tissue Macrophage and T lymphocyte Accumulation and Leads to Insulin Resistance.” PLoS ONE 10 (7): e0131176. doi:10.1371/journal.pone.0131176. http://dx.doi.org/10.1371/journal.pone.0131176.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:17820919Objectives: Angiopoietin-like protein 2 (ANGPTL2), a recently identified pro-inflammatory cytokine, is mainly secreted from the adipose tissue. This study aimed to explore the role of ANGPTL2 in adipose tissue inflammation and macrophage activation in a mouse model of diabetes. Methodology/Principal Findings Adenovirus mediated lacZ (Ad-LacZ) or human ANGPTL2 (Ad-ANGPTL2) was delivered via tail vein in diabetic db/db mice. Ad-ANGPTL2 treatment for 2 weeks impaired both glucose tolerance and insulin sensitivity as compared to Ad-LacZ treatment. Ad-ANGPTL2 treatment significantly induced pro-inflammatory gene expression in white adipose tissue. We also isolated stromal vascular fraction from epididymal fat pad and analyzed adipose tissue macrophage and T lymphocyte populations by flow cytometry. Ad-ANGPTL2 treated mice had more adipose tissue macrophages (F4/80+CD11b+) and a larger M1 macrophage subpopulation (F4/80+CD11b+CD11c+). Moreover, Ad-ANGPTL2 treatment increased a CD8-positive T cell population in adipose tissue, which preceded increased macrophage accumulation. Consistent with our in vivo results, recombinant human ANGPTL2 protein treatment increased mRNA levels of pro-inflammatory gene products and production of TNF-α protein in the human macrophage-like cell line THP-1. Furthermore, Ad-ANGPTL2 treatment induced lipid accumulation and increased fatty acid synthesis, lipid metabolism related gene expression in mouse liver. Conclusion: ANGPTL2 treatment promotes macrophage accumulation and activation. These results suggest potential mechanisms for insulin resistance.en-USJournal Article2015-08-0310.1371/journal.pone.0131176